Renin is a proteolytic enzyme having a molecular weight of about 40,000, produced and secreted by juxtaglomerular cells in the kidney. This acts on the plasma renin substrate, angiotensinogen, to yield decapeptide angiotensin I which is converted into angiotensin II by an angiotensin I converting enzyme.
It is well known that angiotensin II contracts the vascular smooth muscle and acts on the adrenal cortex to secrete the aldosterone which regulates salts and water balance. Accordingly, the renin-angiotensin system plays an important role in hypertension. An effective inhibitor of renin has long been sought as an agent for treatment of hypertension, especially renin-associated hypertension. As a result, it has been found that certain peptides show a renin inhibitory effect, as described in U.S. Pat. No. 4,548,926, Japanese Patent Application (OPI) Nos. 163899/85, 275257/86, 78795/86, 227851/84, 155345/84, 110661/84, (The term "OPI" as used herein refers to an unexamined Japanese patent application); Japanese patent Publication No. 39149/83, Biochemical and Biophysical Research Communications, Vol. 118, pages 929-933, 1984; and European Patent Application Nos. 77029(A.sub.2), 77028(A.sub.2) and 81783(A.sub.2).
Of these prior art references, Japanese Patent Application (OPI) No. 163899/85 discloses peptides represented by the following formula: ##STR1## wherein R.sup.1 CO represents an aliphatic acyl group, an aromatic acyl group, an aromatic aliphatic acyl group, a heterocyclic acyl group or a heterocyclic aliphatic acyl group, said acyl groups being able to have an amino group, a protected amino group, a hydroxy group, a substituted dithio group, an alkyl group, an alkoxy group, an alkoxycarbonyl group, a halogen atom or a nitro group as a substituent;
R.sup.2 represents an isobutyl group or a sec-butyl group; PA1 X represents a group of formula ##STR2## in which R.sup.3 represents a carboxyl group, an N-substituted carbamoyl group, a carbazoyl group, an N-substituted carbazoyl group or an acyl group, A represents a single bond or an alkylene group, Y represents a hydroxy group, a mercapto group or a formyl group, or a group of formula ##STR3## in which R.sup.4 represents a substituted alkyl group having a carboxy group, a protected carboxy group, an N-substituted carbamoyl group, a carbazoyl group, an N-substituted carbazoyl group or an acyl group as a substituent; PA1 His represents an L-histidyl group;
and pharmaceutically acceptable salts and esters thereof.
Japanese Patent Application (OPI) No. 78795/86 also discloses optical isomers of peptides disclosed in Japanese Patent Application (OPI) No. 163899/85.
Japanese Patent application (OPI) 275257/86 discloses peptides closely related to compounds of this invention. Although this reference does not specifically disclose, the compounds having following formula is included within the broad scope thereof: ##STR4## wherein R.sup.5 represents an alkoxy group having 1 to 10 carbon atoms, a mono or di-alkylamino group having 1 to 10 carbon atoms or a heterocyclic group, said heterocyclic group being connected the carbonyl group in the formula with the nitrogen atom in said heterocyclic group, and pharmaceutically acceptable salts thereof.
However, this reference does not teach that compounds having a morpholinocarbonylmethyl group instead of the morpholinoethyl group exhibit an excellent renin inhibitory activity.
Furthermore, with regard to peptides related to those of this invention, the inventors of this invention also have filed some U.S. patent applications Ser. Nos. 789,597 (filed Oct. 21, 1985), 824341 (filed Jan. 31, 1986), 852,260 (filed Apr. 15, 1986), 879,741 (filed June 27, 1986), 903,803 (filed Sept. 14, 1986) and 32,693 (filed Apr. 1, 1987).
On the other hand, by someone of the present inventors and others, analogous peptides to those of this invention have been published in European Journal of Pharmacology, Vol. 129, No. 3, 393-396, 1986, and have been reported in the 50th Annual Scientific Meeting of the Japanese Circulation Society, March, 1986; the 59th General Meeting of the Japanese Pharmacological Society, April, 1986; the 106th Annual Meeting of Pharmaceutical Society of Japan, April, 1986; the 37th Regional Meeting (Kita area) of the Japanese Pharmacological Society, August, 1986; the 2nd annual meeting of the American Society of Hypertension, May, 1987.